The purpose of this study was to investigate whether helium-hyperoxia (HeHOx) would allow greater tolerance to maximal and submaximal exercise compared to hyperoxia (HOx) on isolation in hypoxaemic chronic obstructive pulmonary disease (COPD) patients under long-term oxygen therapy. In a double-blind study, 24 males in the Global Initiative for Chronic Obstructive Lung Disease functional class IV (forced expiratory volume in 1 s 35.2±10.1% predicted and arterial oxygen tension 56.2±7.5 mmHg) were submitted to incremental and constant load cycling at 70-80% peak work rate while breathing HOx (60% nitrogen and 40% oxygen) or HeHOx (60% helium and 40% oxygen). HeHOx improved resting airflow obstruction and lung hyperinflation in all but two patients (p<0.05). Peak work rate and time to exercise intolerance were higher with HeHOx than HOx in 17 (70.8%) out of 24 patients and 14 (66.6%) out of 21 patients, respectively (p<0.05). End-expiratory lung volumes were lower with HeHOx, despite a higher ventilatory response (p<0.05). HeHOx speeded on-exercise oxygen uptake kinetics by ∼30%, especially in more disabled and hyperinflated patients. Fat-free mass was the only independent predictor of higher peak work rate with HeHOx (r(2) = 0.66, p<0.001); in contrast, none of the resting characteristics or exercise responses were related to improvements in time to exercise intolerance (p>0.05). Helium is a valuable ergogenic aid when added to HOx for most long-term oxygen therapy-dependent patients with advanced COPD.